Diabetes mellitus (DM) is a prevalent, costly condition with high morbidity and mortality. Our goal is to determine prospectively mechanisms by which type 2 DM alters cerebral microcirculation and contributes to brain tissue damage and cognitive decline in the elderly. The primary hypotheses are: 1. Hyperglycemia is a common mechanism for microvascular disease, disturbance in blood flow regulation and brain tissue damage in older adults with type 2 DM. 2. Inflammation contributes to neuroanatomical changes in periventricular white matter and white matter hyperintensities on MRI. 3. Cortical and subcortical atrophy in frontal and temporal regions manifests as executive dysfunction and impairment of balance in older adults with type 2 DM. Diabetes severity and higher hemoglobin A1C levels are associated with progressive decline in cerebral blood flow, cortical and subcortical brain volumes, and cognition and balance in older adults with type 2 DM. We will prospectively study 60 diabetic and 60 control subjects (50-85 years old, matched by age and hypertension) at baseline and after a two-year follow-up. In the Aim 1 we will determine the effects of type 2 DM on regional brain tissue volumes and perfusion, dynamics of cerebral autoregulation. In Aim 2 we determine the effects of inflammation on white matter integrity. In the Aim 3 we will determine longitudinally if higher hemoglobin A1C levels increase progression of cerebral blood flow dysregulation, brain atrophy and worsen cognitive and balance outcomes. Regional gray, white matter and cerebrospinal fluid volumes will be quantified using a segmentation method applied on T1- and T2- weighted images and perfusion maps, using a continuous arterial spin labeling (CASL) images at 3 Tesla MRI. White matter integrity will be determined from fluid attenuated inversion recovery (FLAIR) and diffusion tensor imaging (DTI) MRI. Dynamics of cerebral vasoregulation to CO2 challenge and orthostatic stress will be determined using Doppler ultrasound. We plan to use statistical structural equation modeling technique to characterize the mechanisms by which diabetes may lead to cognitive decline in older people, and to quantify interactions among metabolic diabetic disturbance, cerebral blood flow and brain atrophy. This study will provide new data and biomarkers on cerebral perfusion and functional outcomes in type 2 DM that can be used to initialize the efforts to implement brain protection as a new target prevention of DM complications. PUBLIC HEALTH RELEVANCE: Diabetes mellitus (DM) is a prevalent, costly condition with high morbidity and mortality that doubles the risk for stroke and dementia. DM affects blood flow regulation in the brain, that leads to brain damage and worsening of cognition and balance in older diabetic adults. This study will provide new data and biomarkers on cerebral perfusion and functional outcomes in type 2 DM, that can be used to initialize the efforts to implement brain protection as a new target for prevention of DM complications.